Patterns of capsular serotype diversity in Streptococcus pneumoniae show geographic and medium-term temporal consistency. Understanding the mechanisms maintaining this diversity is of basic science interest as pneumococcal capsules are a paradigm case of antigenic diversity, and of public health interest as vaccines with serotype-specific effectiveness change the patterns of pneumococcal carriage and disease. Epidemiologic and experimental findings from our laboratory and others have suggested that immune responses that limit colonization and disease from Streptococcus pneumoniae (pneumococcus) are largely not serotype-specific. These findings raise concerns about the traditional explanation that serotype-specific host immunity maintains the observed patterns of diversity of pneumococcal capsular serotypes. Here we propose experimental tests of three alternate hypotheses for maintenance of capsular diversity: 1) serotype- specific differences in susceptibility to innate immune mechanisms, specifically those mediated by Toll-like receptors;2) serotype-specific differences in susceptibility to acquired immune responses to antigens other than the capsule;and 3) serotype-specific differences in the ability to compete with other pneumococci in colonizing the nasopharynx. Tests of these hypotheses in vivo using mice will be supplemented with in vitro studies in mouse and human cell lines or primary cell isolates to confirm the mechanistic basis of observed results and assess the validity of the animal model for humans. We will also analyze two clinical trial data sets for evidence of host heterogeneity in a tendency to be colonized with particular serotypes, and use mathematical models to assess the ability of these hypothetical mechanisms to maintain capsular diversity.